Many clinically approved drugs originated from natural products. Well-known examples include morphine, penicillin, Yondelis, and erythromycin. Natural product drugs have been isolated from plants, fungus, marine invertebrates, and bacteria.
Actinobacteria are gram-positive, soil-dwelling bacteria. Actinomycetes have been described as the most prolific source of bioactive microbial natural products, making them a valuable resource for the discovery of new secondary metabolites. Members of the genus Kitasatospora, which are classified as rare Actinobacteria, have been shown to produce a wide variety of natural products including bafilomycins, kitasetaline and more recently satosporins.4 Members of this rare and underexplored genus have the potential to produce multiple natural products, which was revealed by genome sequencing of Kitasatospora setae showing the presence of 24 putative secondary metabolite gene clusters. This makes members of this genus ideal microorganisms to investigate for their ability to produce structurally unique and bioactive secondary metabolites.
Kitasatospora cystarginea NRRL-B16505 is a soil dwelling bacterium that was originally isolated in 1988 from Yamaguchi Prefecture, Japan, and was reported to produce the antifungal peptide cystargin. It has also recently been reported to produce the cyclic lipopeptide cystargamide.
The β-lactone class of natural products is a broad class that has a variety of biological activities. Tetrahydroxylipstatin (THL, Orlistat) is a derivative of the natural product lipstatin, and is a β-lactone containing compound that is approved by the FDA as a pancreatic lipase inhibitor used to treat obesity. Other members of this class include belactosin A, salinosporamide A and omuralide, which are all reported to have proteasome inhibitory activity.
The ubiquitin-proteasome pathway plays a major role in eukaryotic cellular protein degradation. This system adjusts the level of proteins involved in regulating cellular processes like signal transduction, immune responses and cell cycle progression. Inhibitors of the proteasome have gained attention for their ability to block cell cycle progression and cause apoptosis, which makes them useful antiproliferative agents. Bortezomib and carfilzomib are proteasome inhibitors that have been approved by the FDA for treatment of multiple myeloma, and several other proteasome inhibitors are currently in clinical trials.
A need exists for additional, alternative, and/or improved natural product-based compounds having biological activity.